EP2259780A2 - Composition pharmaceutique comprenant de la naltrexone - Google Patents

Composition pharmaceutique comprenant de la naltrexone

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Publication number
EP2259780A2
EP2259780A2 EP09715616A EP09715616A EP2259780A2 EP 2259780 A2 EP2259780 A2 EP 2259780A2 EP 09715616 A EP09715616 A EP 09715616A EP 09715616 A EP09715616 A EP 09715616A EP 2259780 A2 EP2259780 A2 EP 2259780A2
Authority
EP
European Patent Office
Prior art keywords
naltrexone
adhesive
transdermal patch
patch
transdermal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09715616A
Other languages
German (de)
English (en)
Inventor
Ludwig Jan Weimann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syntropharma Ltd
Original Assignee
Syntropharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Syntropharma Ltd filed Critical Syntropharma Ltd
Publication of EP2259780A2 publication Critical patent/EP2259780A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • compositions comprising the pharmaceutical naltrexone, an opioid receptor antagonist, and methods of using such compositions, in particular for the transdermal delivery of naltrexone.
  • the compositions and methods of the invention have utility in a number of therapeutic interventions, in particular in the treatment of alcoholism and opiate addiction.
  • Naltrexone is a well-known opioid receptor antagonist with no opioid agonist properties. Low doses of naltrexone have been investigated in patients with multiple sclerosis, autism, active Crohn's disease, AIDS, rheumatoid arthritis, celiac disease, certain forms of cancer, and autoimmune diseases. Opioids act as cytokines, the principal communication signallers of the immune system, creating immunomodulatory effects through opioid receptors on immune cells. Very low doses of naltrexone, of approximately one-tenth the usual dosage, boosts the immune system and helps to fight against diseases characterized by inadequate immune function. However naltrexone is used most commonly in the treatment of alcohol dependence (alcoholism) and opiate addiction.
  • naltrexone blocks the effects of opioids by its highly competitive binding at the ⁇ -opioid receptors. Being a competitive antagonist, the suppression of an opiate's agonistic, euphorigenic effect can be overcome.
  • clinical studies have indicated that naltrexone in an oral dosage of approximately 50 mg is able to block the pharmacological effects of up to 25 mg of intravenously administered heroin for periods as long as twenty four hours.
  • naltrexone in the treatment of alcoholism is not understood although involvement of the endogenous opioid system is suggested by preclinical data. Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone has shown efficacy in maintaining abstinence in clinical studies in humans.
  • naltrexone Although well absorbed orally (approximately 96% of an oral dose is absorbed from the gastrointestinal tract), naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5% to 40%. The activity of naltrexone is believed to be as a result of both naltrexone and its
  • 6- ⁇ -naltrexol metabolite Two other minor metabolites are 2-hydroxy-3-methoxy-6- ⁇ - naltrexol and 2-hydroxy-3-methyl-naltrexone. Peak plasma levels of both naltrexone and 6- ⁇ -naltexol occur within one hour after oral dosing; mean elimination half-life values for naltrexone and 6- ⁇ -naltrexol are four and thirteen hours respectively.
  • naltrexone tablets as an adjunctive treatment of alcoholism, are typically used in a dosing regimen of 50 mg once daily for up to 12 weeks.
  • a flexible approach to a dosing regimen tends to be employed to enhance patient compliance.
  • patients may receive 50 mg of oral naltrexone every weekday, with a 100 mg dose on Saturday, or patients may receive 100 mg every other day, or 150 mg every third day.
  • the systemic daily dose may vary between 2.5 and 20 mg, taking into account the oral dose and the bioavailability of naltrexone.
  • naltrexone Whilst the oral administration of any drug has clear advantages, issues of patient non-compliance are particular concerns with the use of naltrexone in the treatment of alcoholism and for the treatment of opiate addiction.
  • naltrexone is a major liver toxin, which precludes oral administration in a significant number of alcoholics. Its long half-life also has the effect that there are significant quantities of it in the body after a period during the day when an alcoholic undergoing treatment may be permitted to drink.
  • Clinicians generally prefer that a low build-up of an antagonist in the body before a session and its continued presence after the session should be avoided as much as possible.
  • naltrexone is the first new anti-alcoholism drug to receive approval from the Food and Drug Administration in the United States in many years, patient non-compliance, coupled with adverse gastro-intestinal effects, and variation in metabolic effects between even complying patients, limit the clinical usefulness of naltrexone.
  • naltrexone As an alternative to oral administration, the use of depot injections of naltrexone have been investigated but such a way of administering of naltrexone is undesirable.
  • depot injections are highly invasive and have additional pharmacological problems associated with inconsistent initial and sustained rates of delivery, inadequate release rates and site-of injection reactions.
  • injectable naltrexone is indicated or the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment.
  • the recommended dose of 380 mg is administered intramuscularly every 4 weeks (once a month). This equates to an average daily dose is 12.5 mg with such a formulation.
  • naltrexone In the treatment of opiate dependence, a dose of 50 mg once a day produces adequate clinical blockade of the actions of parenterally administered opiates.
  • oral naltrexone is of proven value only when given as part of a comprehensive treatment plan that includes measures to ensure the patient compliance. Naltrexone has very few and minor side effects, and may be the treatment of choice in highly motivated patients.
  • clinical experience using oral naltrexone for treating opiate dependence has been replete with data of poor medication compliance according to several reports.
  • naltrexone whilst naltrexone is available as once-a-day 50 mg oral tablets for the treatment of alcohol dependence and for opiate addiction, and as once-a-month injections for the treatment of alcohol dependence.
  • There is a need to develop alternative non-invasive, controlled-released dosage formulations and methods of delivery for naltrexone as a consequence of the disadvantages reported above in relation to existing modes of naltrexone delivery using oral and injection-based
  • Transdermal administration of drugs is often advantageous: it eliminates first- pass metabolism, and reduces gastro intestinal side-effects, and the invasiveness of the intramuscular depot injections known in the art.
  • naltrexone does not present itself as an optimum or obvious candidate for transdermal delivery. This is, in part, as a consequence of the relatively high dosages required (for example between 2.5 mg and 20 mg per day) and because of a difficulty in achieving permeation through the skin, amongst other drugs.
  • EP-A-178140 Alza Corporation it is reported that the low permeability of naltrexone through the skin led to unsuccessful attempts to increase its permeation by the contemporaneous administration of conventional permeation enhancers.
  • compositions comprising naltrexone and specific penetration enhancers permit the transdermal delivery of therapeutically relevant quantities of naltrexone.
  • compositions comprising naltrexone in combination with the compounds methyl oleate and/or isopropyl myristate are useful in this regard, particularly when incorporated into patches suitable for adhesion to the skin of a patient.
  • the invention provides a composition comprising naltrexone and methyl oleate.
  • the invention provides a transdermal patch comprising an adhesive and a composition comprising naltrexone and methyl oleate.
  • the invention provides a transdermal patch comprising an adhesive and a composition comprising naltrexone and isopropyl myristate.
  • the invention provides a composition according to the first aspect for use as a medicament.
  • the invention provides a composition according to the first or third aspects for use in the treatment of alcoholism.
  • the invention provides a composition according to the first or third aspects for use in the treatment of opiate addiction.
  • the invention provides a method of treatment of a human patient suffering from alcoholism comprising affixing a patch according to the second or third aspects of the invention to the skin of the patient whereby to effect transdermal delivery of naltrexone.
  • the invention provides a method of treatment of a human patient suffering from opiate addiction comprising affixing a patch according to the second or third aspects of the invention to the skin of the patient whereby to effect transdermal delivery of naltrexone.
  • the invention provides a kit comprising a plurality of patches according to the second or third aspects of the invention, wherein said patches are either the same or at least some differ from others in comprising a different quantity of naltrexone.
  • Fig. 1 shows a cross-sectional schematic representation of a fluid-reservoir (Fig. 1(a)), solid-reservoir (Fig. 1(b)) and monolithic (Fig. 1(c)) transdermal patches.
  • Figure 2 is a cross-sectional schematic representation of a liquid-reservoir transdermal patch.
  • Fig. 3(a) shows schematically the coating and lamination steps involved in a process for manufacturing monolithic transdermal patches of the invention and Fig. 3(b) shows schematically the die-cutting of laminates resultant from Fig. 3(a) whereby to afford monolithic patches.
  • Fig. 4(a) shows a schematic view of a manufacturing process of reservoir patches of the invention and Fig. 4(b) shows schematically the same process in plan.
  • Fig. 7 shows the in vitro flux of naltrexone through human cadaver epidermis from different monolithic patches, each containing 10% naltrexone.
  • Fig. 8 shows a comparison of the in vitro flux of naltrexone through human cadaver epidermis from reservoir patches and a monolithic patch based on DURO-TAK ® 87-2510 adhesive with 10% naltrexone (shown as 2510/10).
  • Fig. 9 shows the in vitro flux of naltrexone through human cadaver epidermis from monolithic patches based on DURO-TAK ® 87-2510 adhesive containing 10% naltrexone with different skin penetration enhancers at 5% (shown as 2510/10/X where X denotes the abbreviated name for the enhancer) compared with one reservoir patch (MPM/95/IPM) containing naltrexone-saturated ethanol solution containing 5% isopropyl myristate.
  • MPM/95/IPM naltrexone-saturated ethanol solution
  • Fig. 10 shows the effect of patch and skin temperature on in vitro flux of naltrexone through human cadaver epidermis from monolithic patches based on DURO- TAK ® 87-2510 adhesive containing 10% naltrexone with different skin penetration enhancers at 5% (shown as 2510/10/X where X denotes the abbreviated name for the enhancer) compared with one reservoir patch (MPM/95/IPM) containing naltrexone- saturated ethanol solution containing 5% isopropyl myristate.
  • MPM/95/IPM a reservoir patch
  • FIG. 11 shows in vitro flux of naltrexone through human cadaver epidermis from monolithic patches of DURO-TAK ® 87-2510 containing 10% naltrexone with and without methyl oleate enhancer and from reservoir patch MPM/95/IPM at 32 0 C.
  • Fig. 12 shows in vitro flux of naltrexone through human cadaver epidermis from monolithic patches of DURO-TAK ® 87-2510 containing 10% naltrexone with and without methyl oleate enhancer and from reservoir patch MPM/95/IPM at 42 0 C.
  • naltrexone-containing compositions comprising the compounds methyl oleate and/or isopropyl myristate are effective at permitting transdermal delivery into animals, in particular humans, typically from transdermal patches comprising such compositions that may be affixed to a subject's skin.
  • transdermal herein is meant the passing through the skin and into a subject's blood stream, whereby to provide a systemic effect.
  • transmucosal viz passing through mucosal tissue so as to embrace sublingual, buccal, vaginal and rectal delivery
  • transdermal delivery is effected through a subject's skin.
  • references are generally made herein to skin for simplicity's sake only although it will be appreciated that the transdermal delivery described herein may also be transmucosal.
  • patches herein material adapted for adhesion to a subject's skin or mucosal tissue.
  • patches herein have a substantial degree of rigidity and, in use, comprise a backing layer exposed to the environment and a naltrexone-containing composition beneath the backing layer.
  • the patches of the invention may also be of a non-rigid nature, for example as described in US Patent No. 6,093,419.
  • compositions comprising naltrexone and methyl oleate.
  • Such compositions may be presented in a number of different ways, a typical presentation being one that permits transdermal delivery. Examples of transdermal patches comprising naltrexone and methyl oleate are described hereinbelow.
  • the compositions may be contained within an adhesive patch designed to be affixed to the skin of a patient, or formulated into a capsule or sachet susceptible to easy rupture (e.g. by rubbing or squeezing between fingers) for release of a calculated dose of naltrexone formulation onto the skin into which it may be rubbed.
  • Such sachets or capsules are disclosed in US patent number 5,096,715.
  • compositions of the present invention comprising naltrexone and methyl oleate are presented as adhesive transdermal patches.
  • patches comprising naltrexone and methyl oleate or isopropyl myristate constitute a delivery system for transdermal delivery of the naltrexone contained within them.
  • Adhesive patches for the transdermal delivery of drugs are well known and have been described by H. S. Tan and W. R. Pfister in Pressure-sensitive adhesives for transdermal drug delivery systems, PSTT (Elsevier Science) Vol. 2. No. 2, February 1999.
  • Transdermal patches comprising the compositions of this invention contain a quantity of naltrexone and methyl oleate or isopropyl myristate to be delivered and an adhesive to allow contact between the patch and the skin to be maintained in absence of external pressure.
  • the patches comprise a first face that contacts the skin, and a protective backing layer on a second face of the patch opposing the first face, one face of the backing layer being exposed to the environment during use and comprising a material that is impervious to the components present in the patch.
  • Attached to the first face of a transdermal patch is typically a releasable protective layer that protects the patch prior to its use and which may be released from the adhesive disposed at the first face of the patch prior to the patch being affixed to the skin.
  • transdermal patches according to this invention may be broadly divided into three categories: so-called fluid reservoir, solid reservoir and monolithic types. These are depicted in cross-section in Fig. 1.
  • Fig. 1(a) shows a fluid reservoir patch (1 ), the naltrexone-containing composition contained within being either dissolved or dispersed in a continuous matrix carrier (2), such as a fluid (typically a liquid) or a gel.
  • a continuous matrix carrier (2) such as a fluid (typically a liquid) or a gel.
  • the reservoir may be separated by a permeable membrane (3) from an adhesive layer (4).
  • the rate-controlling membrane may be selected to control the rate at which the reservoir's contents are released to, and then through, the skin-contacting adhesive layer.
  • the protective backing (5) and release (6) layers are also shown.
  • the protective backing may be heat-sealed on the periphery that encloses/captures the liquid inside the reservoir.
  • the solid reservoir may comprise a polymer matrix (8) from which the naltrexone-containing composition may be released.
  • the nature of the polymer matrix in solid reservoir patches may serve to control the rate at which the naltrexone is delivered. Alternatively an optional rate-controlling membrane (3) may be present.
  • Fig. 1(b) also shows the protective backing (5) and release (6) layers.
  • a monolithic patch (9) is shown in (Fig. 1(c)), showing the naltrexone composition and adhesive in intimate admixture (10).
  • the adhesive matrix through which the naltrexone containing composition is dissolved or dispersed may be used to control the rate at which the naltrexone is released, one or more optional rate-controlling membranes (3) may be present to provide a laminate, as opposed to a monolithic, structure.
  • Fig. 1(c) shows a single such a membrane disposed between two layers (10) of adhesive/naltrexone-containing matrix. Alternatively there may be a plurality of such membranes (not shown) whereby to provide a multilaminate structure.
  • the naltrexone- containing compositions are presented in patches of the liquid reservoir, solid-reservoir and monolithic types. These embodiments are therefore now described in greater detail.
  • the monolithic patches are presented in a patch as depicted in cross-section in Fig. 1(c) but without the rate-controlling membrane (13).
  • the monolithic patch construction typically comprises a protective backing layer (5), an adhesive matrix comprising the naltrexone-containing composition (10) and a releasable protecting layer (6) which may be removed, typically immediately prior to use of the patch.
  • the patch of the monolithic type typically comprises two parts: the adhesive- and naltrexone-containing layer; and the protective backing.
  • the releasable protecting layer may be made of any convenient material.
  • Appropriate materials are known in the art and include siliconised polyester or polyethylene materials, such as Scotchpak 9742, manufactured by 3M; and Bio-Release ® and Syl-off ® 7610 liners of Dow Corning Corporation.
  • Other suitable release liners are available from both 3M and Dow Corning Corporation, and from other manufacturers.
  • the naltrexone- and adhesive-containing layer comprises naltrexone and methyl oleate or isopropyl myristate dispersed or dissolved in an adhesive matrix, more particularly a pressure-sensitive adhesive matrix.
  • a pressure-sensitive adhesive is a substance that forms a bond when pressure is applied between it and a surface, with the strength of the bond formed resultant from the amount of pressure used to apply the adhesive to the surface.
  • Suitable pressure-sensitive adhesives to use in transdermal delivery patches are well known to those skilled in the art and have been reviewed, for example, by Tan and Pfister (infra).
  • Three types of adhesive are commonly employed in transdermal patches: polyisobutylenes, silicones and polyacrylate copolymers, although natural or synthetic rubber- or karya gum-based adhesives may also be used.
  • Each of these four types of adhesive are commercially available, for example under the Roderm ® (Rohm and Haas) DURO-TAK ® (National Starch and Chemical Company) and BIO PSA ® (Dow Corning) trade names.
  • Exemplary silicone pressure-sensitive adhesives are based on two major components: a polymer, or gum, and a tackifying resin.
  • the silicone adhesive is usually prepared by cross-linking the gum, typically a high molecular weight polydiorganosiloxane, with the resin, to produce a three-dimensional silicate structure, via a condensation reaction in an appropriate organic solvent.
  • the ratio of resin to polymer is the most important factor, which can be adjusted in order to modify the physical properties of polysiloxane adhesives. (see Sobieski et a/., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989)).
  • Suitable silicone pressure-sensitive adhesives are commercially available and include the silicone adhesives sold under the trademarks BIO-PSA ® by Dow Corning Corporation, e.g. BIO-PSA ® 7-4302.
  • the pressure-sensitive adhesive matrix comprises a polyacrylate copolymer.
  • Such adhesives are used as such on account of their inherent tackiness. They are produced by copolymerisation of acrylic esters, acrylic acid and other functional monomers.
  • polyacrylate copolymer is used interchangeably here with the terms acrylic polymer, acrylate polymer, polyacrylate, polyacrylic adhesive and polyacrylate polymers as it is in the art.
  • Polyacrylates useful in practicing the invention are polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
  • the acrylic polymers also include copolymers of alkyl acrylates and/or methacrylates and/or copolymerizable secondary monomers or monomers with functional groups. By varying the amount of each type of monomer added, the cohesive properties of the resulting polyacrylate can be changed as is known in the art.
  • the polyacrylate is composed of at least 50% by weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer copolymerizable with the acrylate, and from 0 to 40% of other monomers.
  • Acrylate monomers that can be used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2- ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2- ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.
  • Functional monomers, copolymerizable with the alkyl acrylates or methacrylates described above include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert- butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate and other monomers having at least one unsaturated double bond which participates in copolymerization reaction in one molecule and a functional group on its side chain such as a carboxyl group, a hydroxyl group, a sulfoxyl group, an amino group, an amino group and an alkoxyl, as well as a variety of other monmeric units including alkylene
  • acrylic adhesives which are suitable in the practice of the invention are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2 nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989) and are also described by Tan and Pfister (infra).
  • acrylic adhesives are acrylate or acrylate/vinyl acetate copolymers based on aliphatic monoacrylate monomers, e.g. butyl or 2-ethyl-hexyl acrylates and hydroxyl-aliphatic monoacrylate monomers e.g. hydroxyethyl acrylate, and vinyl acetate.
  • An example of such an acrylic adhesive is DURO-TAK ® 87-2510 sold by National Starch Company, Bridgewater, N.J.
  • Suitable acrylic adhesives are commercially available and include the polyacrylate adhesives sold under the trademarks DURO-TAK ® by National Starch Company, Bridgewater, N. J., for example DURO-TAK ® 87-608A, 900A AND 2510;
  • the pressure - sensitive adhesive matrix is a polyacrylate copolymer, since use of such matrices appear to permit higher transdermal fluxes of naltrexone (see the experimental results below). It is not completely understood why this is so; however, and without wishing to be bound by theory, such matrices have generally greater Hildebrand solubility parameters than other adhesives such as rubber-based or silicone adhesives.
  • the Hildebrand solubility parameter which is the square root of the cohesive energy of a substance, and provides an estimate of the degree of cohesion within a material.
  • the Hildebrand solubility parameters quoted herein are calculated in accordance with the method described by Allan F. M. Barton in Handbook of Solubility Parameters and Other Cohesion Parameters, 2 nd ed, CRC Press, 1991 , at page 157. We have surprisingly found that, generally, greater naltrexone fluxes achieved from the compositions of this invention when using adhesives of greater Hildebrand solubility parameter.
  • adhesive matrices are employed that have Hildebrand solubility parameters in the range of 17 (J/cm 3 ) 14 or higher, for example Hildebrand solubility parameters in the range 17 to 25 (J/cm 3 ) 1/2 , more particularly 19 to 25 (J/cim 3 )" 2 , and more particularly still 19 to 21 (J/cm 3 )' /2 .
  • Adhesive matrices having such Hildebrand solubility parameters are typically, although not necessarily polyacrylate copolymers. Where matrices have similar Hildebrand solubility parameters, e.g.
  • the polyacrylate copolymers DURO-TAK ® 87-2510 and DURO-TAK ® 900-A have Hildebrand solubility parameters of 19.7 and 19.5 (J/cm 3 ) 1/2 respectively as opposed to 14.9 (J/cm 3 )' /2 for the silicone adhesive BIO PSA ® 7-4302, (J/cm 3 ) 1/2 the flux of naltrexone has a lower solubility.
  • the solubility of naltrexone in the matrix may be in the range of about 2 to about 10 g of naltrexone/100 g of adhesive matrix, but in certain embodiments the adhesive matrix is chosen such that the solubility of naltrexone in it is less than about 5g/100 g of adhesive, for example less than about 3g/100 g of adhesive.
  • solubility ranges of 2 to 5, e.g.
  • naltrexone per 100 g of adhesive may be contemplated, particularly where the adhesive is [a polyacrylate copolymer], more particularly where such a polyacrylate copolymer has a Hildebrand solubility parameter the ranges of 17 to 25, more particularly still 19 to 25 (J/cm 3 )" 2 described hereinbefore.
  • This data is presented in Example 5 and Figure 7.
  • mucoadhesive polymer may be selected from one or more of sodium carboxymethyl cellulose, polyacrylic acid, such as sold under the designation Carbopol or polycarbophil, polyvinylpyrrolidone, polyethylene oxide, polyvinylmethylether/maleic anhydride copolymer, methyl cellulose, methylethyl cellulose, polyacrylamide, polyethyleneglycol, polyvinylalcohol, polyhydroxypropylcellulose and polyhydoxymethacrylate.
  • the rate-controlling membrane (3) may be any of those known to those skilled in the art. Suitable materials from which the rate-controlling membranes may be made include, but are not limited to, polyethylene; polypropylene; ethylene/propylene copolymers; ethylene/ethylacrylate copolymers; ethylene/vinyl acetate copolymers; polyacrylates; polymethacrylates; silicone elastomers; medical- grade polydimethylsiloxanes; neoprene rubber; polyisobutylene; chlorinated polyethylene; polyvinyl chloride; vinyl chloride-vinyl acetate copolymer; polymethacrylate polymer (hydrogel); polyvinylidene chloride; poly (ethylene terephthalate); butyl rubber; epichlorohydrin rubbers; ethylene-vinyl alcohol copolymer; ethylene-vinyloxyethanol copolymer; silicone copolymers, for example polysiloxane-polycarbonate
  • Examples include the 9% EVA rate-controlling membrane sold by 3M as CoTran 9702, or the microporous membrane sold by Solutech as Solupor 10P05A.
  • Other rate-controlling membranes are known to those skilled in the art and/or are commercially available.
  • rate-controlling, or permeable, membranes have a porosity of 0.1 to 1 A, e.g. about 0.5A.
  • the backing layer can be any suitable material that is impermeable to the contents of the reservoir compartment, the polymer matrix, or the adhesive matrix.
  • Suitable materials for backing films are well known to those skilled in the art and include, but are not limited to, occlusive polymers such as polyurethane, polyesters such as poly(ethylene phthalate), polyether amide, copolyester, polyisobutylene, polyesters, high and low density polyethylene, polypropylene, polyvinylchloride, metal foils, and metal foil laminates of suitable polymer films.
  • Such backing films are commercially available, e.g. under the Scotchpak ® trade name from 3M, for example the 2 mil LDPE/PET laminate sold as Scotchpak ® 9733.
  • the releasable (6) and non-releasable (5) protecting layers of such patches may be of the same materials as described hereinbefore in respect of the corresponding layers of the monolithic type patches.
  • the principal differences between the monolithic and liquid reservoir type patches is the presence in all embodiments of the latter (as opposed to only certain embodiments of the former) of a rate-controlling membrane and, of course, the presence of a solid or liquid reservoir comprising the naltrexone- containing composition.
  • the adhesives used in such patches may be selected from the same adhesives described above in connection with the adhesives described in relation to the monolithic type patches, in particular the polyacrylate, silicone and adhesives described above, the adhesive is typically a silicone or rubber, e.g.
  • the rate-controlling membrane may be any of those described above in connection with the monolithic type patches.
  • the matrix will be a fluid (normally liquid) matrix although it will be appreciated that polymeric matrices of the types described hereinabove may also be used.
  • naltrexone-containing reservoir is a solid reservoir this may be made from a pharmacologically or biologically acceptable polymer matrix.
  • the polymers used to form the polymer matrix are those capable of forming thin walls or coatings through which naltrexone can pass at a controlled rate.
  • a non-limiting list of suitable materials for use as the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylenevinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluorethylene
  • the naltrexone-containing reservoir is a liquid reservoir
  • this generally comprises a pure or aqueous alcohol, glycol or polyol, or mixture thereof.
  • the liquid reservoir comprises aqueous ethanol or aqueous isopropanol, most typically aqueous ethanol, in which the naltrexone and methyl oleate or isopropyl myristate may be dissolved.
  • aqueous solutions comprising from about 5% to 95% v/v ethanol and from about 95% to 5% v/v water may be used, e.g. about 40% to 60% v/v ethanol and from about 60% to 40% v/v water.
  • aqueous solutions will comprise between about 80 and 95% v/v ethanol.
  • the reservoirs typically comprise naltrexone at saturated concentrations (generally achievable by using 5% to 15% naltrexone) with the dosage rate from the patch being determined not so much by the concentration of naltrexone in the solution but more or entirely by the porosity of the rate-controlling membrane.
  • subsaturated concentrations of naltrexone may be employed with the rate being controlled by the concentration of the naltrexone as well as the porosity of the rate controlling membrane.
  • the quantity of naltrexone that may be used may be in a broad range from about 1 % to about 15% or more, e.g.
  • naltrexone up to about 20% or even more, e.g. about 30% or 40%. These amounts are weight percentages with respect to the weight of the solid or liquid matrix within which the naltrexone is dissolved or dispersed. At concentrations in excess of 10% w/w, the naltrexone in the solid or liquid matrix tends to be past its saturation point and the matrices may contain crystallised, undissolved or precipitated naltrexone. This is an indication that the matrix is saturated and that the greatest transdermal flux is being achieved.
  • a monolithic matrix may be constructed by preparing a liquid adhesive solution or dispersion comprising, as an example, 40% solids and 60% solvent (e.g. aqueous ethanol), as well as dissolved or dispersed naltrexone.
  • the monolithic patches may be made by drying such a preparation in an oven.
  • the resultant matrix comprises 10 g of naltrexone and 90 g of adhesive - it will additionally contain methyl oleate or isopropyl myristate and, generally, a desired amount of solvent - such a concentration of naltrexone is referred to herein as 10 wt %.
  • hydrogels are macromolecular networks that absorb water and thus swell but do not dissolve in water. That is, hydrogels contain hydrophilic functional groups that provide for water absorption, but the hydrogels are comprised of crosslinked polymers that give rise to aqueous insolubility.
  • hydrogels comprise of crosslinked hydrophilic polymers such as polyurethanes, polyvinyl alcohols, polyacrylic acids, polyoxyethylenes, a polyvinylpyrrolidones, a poly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixture thereof.
  • a liquid reservoir may comprise a gelling agent, such as methyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, carboxyvinyl polymer.
  • a gelling agent such as methyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, carboxyvinyl polymer.
  • Such gels may be thixotropic, which can be advantageous during patch manufacture.
  • the amount of isopropyl myristate or methyl oleate affects the transdermal flux of naltrexone from all the formulations of naltrexone described herein. Accordingly, it will be understood that the amount of isopropyl myristate or methyl oleate can be varied to obtain a desired rate of transdermal flux of naltrexone.
  • Typical amounts of isopropyl myristate or methyl oleate are from 1 to 20%, more usually 2 to 10%. These amounts are w/v with respect to the volume of solution used in the liquid reservoir embodiments and w/w with respect to the weight of the solid reservoir or adhesive matrix in the solid reservoir and adhesive matrix embodiments respectively.
  • naltrexone is presented in a composition comprising methyl oleate
  • this presentation is in intimate admixture with an adhesive.
  • the type of patch within the composition is contained, for use in transdermal delivery, is a patch of the monolithic type.
  • the adhesive present in the monolithic matrix comprising adhesive and naltrexone-containing composition is an acrylate adhesive.
  • naltrexone is delivered from a composition comprising isopropyl myristate contained within a transdermal patch
  • this is preferably from a patch of the liquid reservoir type.
  • liquid reservoir- containing patches comprise naltrexone and isopropyl myristate comprises a rate- controlling membrane having pore sizes within the range of about 0.1 to 1A.
  • liquid reservoir-containing transdermal patches of the present invention employ a silicone adhesive although the other adhesives described herein may also be used.
  • the size of the patches may vary from about 1 cm 2 to greater than 200 cm 2 ; typically, patch sizes will cover an area of skin of approximately 5 to 50 cm 2 .
  • adhesive matrix systems can be prepared by casting a fluid admixture of adhesive, and solution or other mixture of naltrexone-containing composition onto the backing layer, followed by lamination of the release liner so as to provide a monolithic patch.
  • the monolithic admixture may be cast on to the release liner, followed by lamination by the backing.
  • the patch may be prepared in the absence of the naltrexone-containing composition, with the composition then added to the patch, for example by soaking aqueous ethanolic solution comprising naltrexone into a polymeric matrix adding such a solution to a void contained with the patch which may then be sealed. Exemplary manufacturing methods are described in the experimental section hereinafter.
  • an adhesive overlayer which may also serve as the backing layer of the patches, may be used to secure the patch to the skin more robustly.
  • Such overlayers may be of such a size that they extend beyond the drug-containing reservoir or matrix such that the adhesive on the overlayer comes into direct contact with an area of the skin surrounding the area of skin to which the naltrexone is delivered from the patch.
  • the presence of such an overlayer can be useful where patches are to be worn by a patient for a prolonged period of time where the adhesive present in the patch might lose some of its adhesion due to hydration.
  • the patch can remain in place for a longer period of time.
  • the adhesive layer of the patch fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive tape, e.g., surgical tape.
  • the transdermal patch it is appropriate to "operate", or use, the transdermal patch at an elevated temperature.
  • liquid reservoir-containing transdermal patches in particular, it has been found that those containing naltrexone and isopropyl myristate effect twice as much delivery of naltrexone when the temperature of the patches increased from 32 0 C to 42 0 C.
  • the ability to provide an elevated temperature to transdermal patches is known to those skilled in the art.
  • One example is a thin patch-like device placed over a medicament-containing transdermal patch, the overlaid secondary patch having a heat-generating system capable of maintaining the transdermal patch beneath at a constant elevated temperature.
  • the release liner is removed to expose the adhesive layer, be it a discrete layer or portion of adhesive as found, for example in the liquid or solid matrix patches described herein, or in admixture with a naltrexone-containing composition, as for example described in relation to the monolithic patches.
  • the adhesive-containing layer is pressed against the skin of a subject to enable the naltrexone to penetrate through the skin of the subject.
  • the delivery rate of the naltrexone is generally controlled by the rate at which naltrexone passes through the rate-controlling membrane; with the monolithic and solid reservoir patches, the delivery rate generally as determined by the rate of diffusion of the naltrexone out of the solid (e.g. polymeric) matrix or naltrexone-containing adhesive composition.
  • naltrexone-containing compositions of the present invention may be administered to a patient in need thereof, in particular as part of a programme of medical intervention associated with the treatment of alcoholism or opiate addiction.
  • alcoholism or opiate addiction are conditions ascertainable by medical practitioners and as used herein references to alcoholism or opiate addiction are to be understood as meaning a condition in which a subject is reliant upon alcohol or opiates to an extent that medical intervention is deemed to be appropriate by a medical practitioner.
  • the dosing regimen administrable by provision of the transdermally deliverable composition of the invention may be determined by an appropriate medical practitioner and that the dosage forms, and in particular the transdermal patches described herein, may contain varying amounts, or concentrations, of naltrexone. Patches or other transdermal ⁇ deliverable compositions of this invention may be administered to any convenient area of skin on the patient. For example patches described herein may be applied to the arm, leg, back, front or other position upon a patient's body.
  • kits of the invention provide a plurality of patches at set dosages, wherein the dosages are set according to the needs of the patient.
  • the patches may contain the same or different quantities or concentrations of naltrexone and may or may not be marked accordingly.
  • Printed instructions on how to apply the patch, storage of the unit, and details of the treatment regimen may also be included in the kits.
  • the kit may also be supplied with a overlying, heating patch as described hereinbefore, for use with the patches of the invention. Alternatively, one or more, e.g. all, of the patches of the kit may comprise such a heating patch.
  • a kit of the invention preferably includes packaging and printed instructions for its use, e.g., on the packaging or package insert.
  • the naltrexone-containing patches within the kit may or may not be coded (i.e., colour, numerical by day, or numerical by dose, etc.) for the patient.
  • the printed instructions may describe the use of the dosage regiment to treat or prevent diarrhoea or other gastrointestinal conditions or disorders.
  • the kit may include a disposal container i.e., any receptacle for holding material or device for disposal of used patches. Any such containers or devices known in the art can be used to prevent or limit potential abuse of the drug within the patch.
  • the delivery profiles vary between different types of transdermal delivery patches.
  • the monolithic transdermal patches described below comprise a pressure-sensitive adhesive matrix containing dissolved/dispersed naltrexone at a concentration close to saturation.
  • a siliconised polyester release liner provided with a slit to aid in its removal prior to use.
  • a typical manufacturing process for monolithic transdermal patches is as follows:
  • Naltrexone optionally powdered, is added to an alcoholic solution, such as aqueous ethanol or aqueous isopropyl alcohol, typically whilst mixing.
  • the naltrexone is present at such a concentration that a homogeneous mixture results.
  • the methyl oleate or isopropyl myristate may be added during this first mixing step or during a subsequent mixing step in which the naltrexone-containing solution with a solution is contacted of adhesive whilst mixing, with mixing being continued until the mix is homogeneous.
  • Fig. 3(a) The coating and lamination procedures are illustrated in Fig. 3(a) in which wound siliconised 3 mil polyester liner (50) is unwound and a mixture of liquid adhesive with naltrexone and methyl oleate or isopropyl myristate (51 ) is added to the unwound release liner by a coating device the knife component of which is shown as (52). The action of the knife component (52) results in a thin layer (53) of the desired monolithic matrix. This then passes into a drying oven (54). The temperature is set in the drying oven at about 150 0 F. To begin the coating procedure, the oven is turned on. Oven air impingement rate and air exhaust is set according to established values.
  • the adhesive blend containing dissolved or dispersed naltrexone is poured into the coating head (not shown).
  • the coater's web is put in motion.
  • the liquid layer of the adhesive blend is laid down (51 ) on the siliconized polyester by means of the coating knife (52) that allows consistent thickness of the liquid adhesive layer.
  • the liquid adhesive layer on the polyester release liner when passing through the oven dries while the solvents evaporate completely forming a solid, tacky layer.
  • the resultant laminate (60) is known as a "patch laminate".
  • a sample of the laminate is cut from the web and weighed to determine if product has the optimum coating weight determined by a specification for the intermediate patch laminate (60).
  • Samples of the patch laminate (60) are also analyzed for drug content and residual solvents can be found (61 ).
  • Fig. 3(b) shows unwinding of the patch laminate from the unwind shaft (62) of a die-cutting machine before the patch laminate (60) passes to the die or dies (63) where patch laminate (60) is cut to provide monolithic transdermal patches (9). These may be placed in pouches (not shown). Winding of the webbed waste laminate (64) is shown at winding station (65).
  • the liquid reservoir transdermal patches described below comprise components as illustrated in Figure 2 wherein 6 is a release liner (Scotchpak 9742 (3M)); 4 is a skin contact adhesive (BIO PSA ® 7-4302 (Dow Coming)); 3 is a drug permeable membrane (either 9% EVA, rate controlling membrane (CoTran 9702 from 3M) or microporous membrane (Solupor 10P05A from Solutech)); 5 is an occlusive backing laminate (2 mil LDPE/PET Scotchpak 9733 from 3M); and is a saturated solution of naltrexone in ethanol.
  • 6 is a release liner (Scotchpak 9742 (3M)); 4 is a skin contact adhesive (BIO PSA ® 7-4302 (Dow Coming)); 3 is a drug permeable membrane (either 9% EVA, rate controlling membrane (CoTran 9702 from 3M) or microporous membrane (Solupor 10P05A from Solutech)
  • the materials used in the construction of reservoir-type transdermal patches are:
  • a controlled membrane laminate which is a laminate of 3 mil PET release liner, 2 mil pressure-sensitive adhesive and 2 mil heat-sealable membrane film (typically 9% EVA or microporous LDPE);
  • a backing film typically a heat-sealable polyester film composed of 1 mil LDPE and 2 mil PET;
  • a gelled naltrexone-containing solution typically the naltrexone-containing solution is present in aqueous alcohol rendered thixotropic by the presence of a gelling agent.
  • Typical gelling agents are hydroxyethyl cellulose, polyacrylic acid and sodium carboxymethyl cellulose. Others will be known to those skilled in the art.
  • a typical manufacturing process is shown schematically in Figure 4.
  • Fig. 4(a) shows the process schematically in elevation
  • Fig. 4(b) shows the process schematically in plan.
  • FIG. 4(a) and 4(b) show the unwinding of the controlled membrane laminate (20).
  • the EVA membrane side (21 ) and PET side (22) of the unwound controlled membrane laminate (20) (23) are shown as the laminate advances towards pump station (24) delivering the typically thixotropic naltrexone-containing solution (25) in aliquots (26) onto the EVE membrane side (21) of the controlled membrane laminate (23).
  • a reel (27) of backing film is unwound prior to heat-sealing within a heat-sealing station (28) having a given patch size tooling set.
  • the heat-sealed package (29) with entrapped drug solution (30) then processes to a first die-cutting station (31 ) which kiss- cuts the package (29) on the EVA membrane side (21).
  • the waste EVA membrane is collected (32) and the kiss-cut package (33) processes to a second die-cutting station (34) which effects cutting of the oversized release liner to afford the desired transdermal patch (1 ) optionally with an oversized release liner (35).
  • Release liner waste (36) is collected (37).
  • Transdermal flux of naltrexone was the highest from the reservoir patch constructed with the microporous membrane and filled with a saturated solution of naltrexone in 95% Ethanol. During the first 24 hrs it has been found to be
  • naltrexone transdermal flux results from reservoir patch formulations show a "burst" effect evidenced by the highest flux occurring during the initial 24 hours with about a 30% flux decrease but, nevertheless, at steady state over the next 4 days.
  • Adhesives used (Hildebrand solubility parameter, in (J/cm 3 ) /2 in parentheses): a. DURO-TAK ® 87-608A (16.6) (PIB Rubber) National Starch b. DURO-TAK ® 900A (19.5) (Acrylic) National Starch c. DURO-TAK ® 87-2510 (19.7) (Acrylic) National Starch d. BIO PSA ® 7-4302 (14.9) (Silicone) Dow Corning e. Roderm ® MD-153 (17.6) (Styrene) Rohm and Haas
  • transdermal fluxes achieved are plotted in Figure 7 which shows that two formulations show the best transdermal flux of naltrexone over 5 days after the first day, namely DURO-TAK ® 87-900A (9.2 mg/24 hrs/40 cm 2 ' and DURO-TAK ® 87-2510 (12.4 mg/24 hrs/40 cm 2 ). All monolithic patches tested show a lag time of about 10 hours. However, after the first 24 hours the naltrexone flux holds at steady state for the next 4 days.
  • the in vitro flux of naltrexone from reservoir patch filled with ethanol saturated solution of naltrexone with 5% IPM enhancer is about 50% higher than the naltrexone flux from a monolithic patch based on DURO-TAK ® 87-2510 adhesive.
  • MO methyl oleate
  • the naltrexone flux from the reservoir patch formulation containing saturated naltrexone solution in ethanol and 5% IPM is the highest.
  • Figure 11 shows in vitro flux of naltrexone through human cadaver epidermis from monolithic patches of DURO-TAK ® 87-2510 containing 10% naltrexone (saturated level) with and without methyl oleate enhancer and from reservoir patch MPM/95/IPM at 32 0 C.
  • Figure 12 shows in vitro flux of naltrexone through human cadaver epidermis from monolithic patches of DURO-TAK ® 87-2510 containing 10% naltrexone (saturated level) with and without methyl oleate enhancer and from reservoir patch MPM/95/IPM at 42 0 C.
  • CONCLUSIONS: 5 Increase of temperature of the transdermal patch and skin by 1O 0 C
  • naltrexone flux (from 32 0 C to 42 0 C) increases in vitro transdermal flux of naltrexone from monolithic patch without enhancers, naltrexone flux almost doubles from monolithic patch of DURO-TAK ® 87-2510 adhesive matrix containing 10% naltrexone (saturated) without an enhancer. 0 2.
  • Naltrexone flux from monolithic patch of DURO-TAK ® 87-2510 adhesive matrix with 5% methyl oleate as an enhancer is not affected by increase of the temperature.
  • Naltrexone flux from reservoir patch filled with ethanol-saturated solution of naltrexone and 5% IPM doubles when the temperature is increased from 32 0 C to 5 42 0 C.

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Abstract

La présente invention concerne des timbres transdermiques constitués d’un adhésif et d’une composition contenant de la naltrexone et de l’oléate de méthyle ou du myristate d’isopropyle, une trousse contenant une pluralité de tels timbres transdermiques, une composition contenant de la naltrexone et de l’oléate de méthyle, une telle composition étant destinée à être utilisée en tant que médicament, et des compositions contenant de la naltrexone et de l’oléate de méthyle ou du myristate d’isopropyle, l’ensemble étant destiné à être utilisé pour le traitement de l’alcoolisme ou d’une dépendance aux opiacés.
EP09715616A 2008-02-28 2009-02-26 Composition pharmaceutique comprenant de la naltrexone Withdrawn EP2259780A2 (fr)

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WO2009106831A3 (fr) 2009-10-29
US20110064788A1 (en) 2011-03-17
US10729686B2 (en) 2020-08-04
WO2009106831A2 (fr) 2009-09-03
JP2011513287A (ja) 2011-04-28
US9700552B2 (en) 2017-07-11
US20170281562A1 (en) 2017-10-05

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